Integrin Alpha v Beta 6  in Cancer Treatment: History
Please note this is an old version of this entry, which may differ significantly from the current revision.

Integrins are necessary for cell adhesion, migration, and positioning. Essential for inducing signalling events for cell survival, proliferation, and differentiation, they also trigger a variety of signal transduction pathways involved in mediating invasion, metastasis, and squamous-cell carcinoma. Several recent studies have demonstrated that the up- and down-regulation of the expression of αv and other integrins can be a potent marker of malignant diseases and patient prognosis.

  • integrin
  • αVβ6
  • cancer treatment
  • integrin beta 6 (INGB6)

1. Implication of INGB6 in Cancer and Its Progression

There is an increasing interest in αvβ6-associated cancers due to high levels of αvβ6 expressions detected in many kinds of epithelial cancers, such as carcinomas of the skin, stomach, colon, breast, lung, oral mucosa, cervix, salivary gland, liver, ovary, and endometrium. The high expression of αvβ6 is mostly affiliated with metastasis and tumour invasion, and with a remarkable decrease in the median survival timings of the patients. Therefore, the high-level expression may work as a prognostic indicator for severe disease, low patient survival, and insignificant tumour differentiation. As αvβ6 has a central role in the pathological course, its activity and expression have been extensively reviewed [1][2][3]. Various molecular mechanisms involving signalling cascade pathways contribute to the overall perfect functioning of the integrin αvβ6.
This αvβ6 is generally accepted as a suppressor of the tumour process in healthy epithelial cells through its anti-proliferative actions by activating the TGF-β1 in these cells. A scientific study on ITGB6 knockout animals disclosed that they did not develop any symptoms of malignant or even benign tumours [4]. In the course of tumour development, together with genetic and epigenetic manipulations, the obscure balance between αvβ6 and TGF-β1 goes uncoupled, resulting in inoperative TGF-β1-mediated signalling pathways where TGF-β1 changes from tumour suppressor to tumour promoter [5]. Consequently, both αvβ6 and TGF-β1 are linked to the tumour process when present in excess amounts in the body. The disruption of the homeostasis maintained between them has been proposed to occur through various mechanisms. The well-studied explanation for the loss of the growth inhibitory action of TGF-β1 is the mutations that occur in growth regulatory genes, e.g., the c-MYC mutation has been most frequently identified in human cancers [6].
Most actions of TGF-β1 are elicited through the canonical SMAD/non-SMAD pathway, but in the case of mutation in any regulatory signalling molecule, TGF-β1 redirects its actions by adopting other transduction pathways [7]. In addition, the commonly occurring oncogenic activation of extracellular signal-regulated kinase (ERK) pathway/mitogen-activated protein kinase/Ras/epidermal growth factor (EGFR) may also cause attenuation of the SMAD pathway by intervening and inhibiting the phosphorylation of the SMAD2/3 linker region [8]. Generally, the SMAD3 linker region undergoes phosphorylation in response to cancer and replaces the aberrant actions of TGF-β1 [7]. It is also possible that the signalling pathways independent of TGF-β1 control the ITGB6 expressions in cancerous cells. As an example, STAT3, which is a transcription factor constantly activated during different cancers, regulates ITGB6 as well as several other genes that perform a role in cell proliferation, invasion, survival, and angiogenesis. STAT3 may also cause an attenuation of TGFβ1-mediated growth inhibition and transcription inside epithelial cells by directly interacting with the SMAD3 pathway, and as a result, an anti-suppressing effect appears [9]. Another factor, Ets-1, is found to be up-regulated in the tumour process, wherein it boosts the ITGB6 expression and cell invasions [10][11]. There is an alternative mechanism of TGF-β1 activation other than by the integrin αvβ6: TGF-β1–uPA interaction in which TGF-β1 promotes the expression of urokinase plasminogen activator (uPA), which in turn activates the latent TGF-β1 complex by plasminogen activation [12].
The key to TGF-β1 transformation from tumour suppressor into promoter in various malignant cancers lies in the robust activation of the Ras-ERK signalling pathway [5]. Eventually, TGF-β1 accompanied by other growth factor signalling cascades can stimulate Epithelial-Mesenchymal Transition (EMT) in carcinoma cells. This transition permits them to relax their organization, producing a more subtle mesenchymal phenotype which facilitates the invasion. EMT induces Ets-1, which then activates the ITGB6 transcription, αvβ6 expression, and latent TGF-β1 complex [10]. The role of integrin αvβ6 goes further than the activation of TGF-β1, as its expression alone can impact the carcinoma cell phenotype. In a study on CRC cells, the overexpressed αvβ6 along with 708 expressed proteins including potential 54 cancer biomarkers, was found to increase cell proliferation and invasion, determining the deep effect of this protein receptor on carcinogenic cell biology. Notably, the defined role of EMT includes invasiveness into cultured epithelia cells, as demonstrated by experimental 3D invasion models as well as animal tumour models. Thus, the necessity of EMT for in vivo metastasis poses technical challenges, and this area attracts scientific investigations [13].
Pro-invasive proteins are clustered by the active functioning of αvβ6 at the tumour-infiltrating edge. These proteins gather uPA and TGF-β type II receptors and move the proteolytic signalling activities of PA cascade and TGF-β1 towards the tumour front, invading their surroundings [10][11]. The central role of integrin αvβ6 in tumour invasion is mainly performed by the intracellular cytoplasmic tail of the β6 subunit. The β6 subunit is directly targeted by ERK2 during the ERK activation in cancerous cells [14][15]. If this binding is prevented, cancer growth will be inhibited. In a similar way, Matrix metalloproteinases MMP-3 and MMP-9 that undergo induction and then activate the cancerous invasion are also dependent on the β6 cytoplasmic tail. Their induction can be abolished by knocking-down Ets-1 or by inhibiting the Ras/ERK pathway. MMP-2 induction is also carried out through Ets-1-dependent β6-mediated mechanisms. Another molecule, psoriasin (S100A7), may also participate in the αvβ6-based carcinoma invasions by binding to the integrin β6 cytoplasmic tail [1].
As a receptor to the extracellular matrix (ECM), αvβ6 also proceeds the cancerous cell migration on the ECM. High fibronectin expressions are linked with advanced stage tumours [16]. In a research study, in vitro experiments were performed on breast cancer cells where they found the integrin αvβ6 promoting the cell migration and invasion localized on MMP-9 degraded fibronectins, also assisting in the metastasis of cancer cells through fibronectin-mediated extravasations. Tenascin-C is another ligand that has been observed with integrin αvβ6 at the invasive tumour front in cancers, and it offers poor clinical outcomes in the case of severe malignant conditions [1].
A study has shown the possible migration of αvβ6 between the prostate cancerous cells through cell-derived vesicles, which are further taken up by the recipient cells deficient in integrin αvβ6. This protein becomes localized on the cell surfaces. Such paracrine-fashioned transportation of the αvβ6-affiliated malignancies makes the metastatic behaviour of tumour cells feasible to the neighbour cell [1]. Table 1 summarizes the mechanistic implications and role of αvβ6 upon expression in different cancers.
Table 1. Mechanistic implications and role of αvβ6 upon expression in different cancers.
Cancer Functions
Endometrial Promotes invasiveness [16]
Basal Cell Promotes invasiveness [17]
Liver Poor prognosis [18]
Colon Cancer Involved in cell adhesion and migration, activation of TGF-B, regulation of extracellular proteases, poor prognosis marker and implications in cancer metastasis to liver [18][19][20][21][22][23]
Gastric Prognostic marker [24]
Cervical Squamous Unfavourable marker [25]
Oral SCC Increased expression in invasive stage of the cancer, regulation of migration and adhesion of cancer cells [26][27][28]
Pancreatic Enhanced expression, regulation of tumour angiogenesis [29][30]
Breast EMT induction and invasiveness [31][32]
Ovary Enhanced expression leads to promotion of metastasis [33][34]

2. Integrin αvβ6 as a Target for Imaging and Therapy

As the integrin αvβ6 expresses with undetectable levels in normal healthy tissues and with high prevalence in invasive tumour cells, it may act as a potential target for tumour imaging and clinical investigations, leading to early diagnostics and therapeutics [2][35]. It also serves as a prognostic marker for tracking pre-invasive tumour progression (e.g., in ductal carcinoma) and monitoring the treatment. Due to its vital role in tumorigenesis, it is a promising target for different treatment approaches. Effective targeting compounds/agents are being developed to perform tumour imaging and delivering therapeutic drugs to cancerous cells [1]
Numerous potential anticancer strategies based on integrin αvβ6 have already been developed and some of them are described here. Immunoliposomes are the vectors used for intracellular targeted drug delivery. In the first step, antibodies (monoclonal or polyclonal) are attached to the liposomal surface and then, recognizing specific antigens, these bind onto tumour cell surfaces. The next step internalizes this drug vector and the targeted drug released in the intracellular compartments. Due to high specificity for drug release, immunoliposomes can deliver large quantities of drugs into cancer cells with the least side effects. In a study on colon cancer, immunoliposomes targeting ITGB6 were developed by combining ITGB6 monoclonal antibodies with PEGylated liposomes. These liposomes successfully delivered the antibodies into ITGB6-positive tumour cells and provided an efficient strategic approach for targeted drug delivery [2]. Two selective, potent monoclonal antibodies 6.8G6 and 6.3G9 were generated, which have high affinity for the human and mouse integrin αvβ6. These block αvβ6 for TGF-β LAP and prevent its activation. These can also block αvβ6-fibronectin interaction, thus, blocking the integrin αvβ6-mediated functions. Neither antibody could bind αvβ6 simultaneously, indicating that they may possess specificities for the overlapping epitopes [36][37][38]. Zhao-yang et al. used a mouse-anti-human β6 function-blocking monoclonal antibody 10D5 to block integrin αvβ6 and found the expression of the phosphorylated extracellular signal-related kinase (P-ERK) significantly decreased. ERK-activation has shown anti-apoptosis effects in colon cancer cells. Integrin αvβ6 plays a vital role in apoptosis-inhibition during cancer and has a significant impact on the mitochondrial pathway [39]. In another study on 10D5-mediated integrin αvβ6-blocking, tumour cell migration, as well as ERK activation, were markedly inhibited, both of which are usually induced by VEGF. Exposing the cells to β6 function-blocking 10D5 antibody inhibits 75% cell migration, in comparison with that observed in the healthy control group [40]. During a rationalized approach, a humanized scFv (single chain Fv) antibody, B6-3, was synthesized with therapeutic potential, causing αvβ6-blockage, which inhibits tumour cell invasion. This antibody can be used for the specific delivery and internalization of the cargo, e.g., toxins specific to αvβ6-expressing cancers [41].
A potential αvβ6-based therapy is human antibody 264RAD, which is highly specific for the integrin αvβ6, blocking the binding of the receptors with their cognate ligands and thereby inhibiting the αvβ6 biological functions. Hence, this therapy remarkably suppresses tumour proliferation and survival [5][42]. In another research study, 264RAD antibody has also demonstrated its effectiveness in reducing tumour growth as well as enhancing the therapeutic effect in combination with trastuzumab in breast cancer [2]. The novel recombinant B6.3 diabody antibody binds specifically to αvβ6 in vitro and targets the specific αvβ6-expressing tumours in vivo. This diabody was engineered with a C-terminal hexahistidine tag (His tag), which was purified by immobilized metal affinity chromatography (IMAC) from Pichia pastoris. The ligand-mimicking diabody elicited αvβ6 internalization upon binding, and effectively blocked αvβ6-dependent adhesion and migration to fibronectin and LAP. It suppressed smad2/3 nuclear translocation upon treatment with latent TGFβ1. The function-blocking ability and target-specificity make the B6.3 diabody either a potent imaging agent or a potential source for the generation of therapeutics through a chemical coupling of small cytotoxic molecules or the addition of toxic agents [43]. These studies proved that αvβ6 is a potential and promising anticancer therapeutic target for clinical practices. In a very recent study on pancreatic cancer, an FMDV-peptide drug conjugate SG3299 was developed by combining αvβ6-specific 20mer peptide from the VP1 coat protein of foot-and-mouth-disease virus (FMDV) with the DNA-binding pyrrolobenzodiazepine (PBD)-based payload SG3249 (tesirine). This resultant conjugate exhibited αvβ6-specificity and -selectivity in vivo and in vitro, as well as showing promising outcomes in selectively eliminating the αvβ6-positive tumour, providing a novel molecular therapy for the patient with pancreatic cancer [44].
Another example is the use of anti-αvβ6 antibodies in combinational therapy in αvβ6-expressing colorectal cancer. The antibody-mediated inhibition of integrin αvβ6 initiated a potent cytotoxic T-cell response and overcame resistance to programmed cell death protein 1 (PD-1)-targeting therapy, provoking a substantial increase in anti-PD-1 treatment efficacy [45][46][47].
Considering the differential expression, αvβ6 integrin is believed to be a novel target for cancer imaging. A series of experimental methods have been devised in various studies, most of which comprise molecular imaging, e.g., single-photon emission computed tomography (SPECT) and positron emission tomography (PET) [48]. As a preclinical development in a recent study, the [18F] αvβ6-binding peptide was used for αvβ6-based imaging through first-in-human (non-invasive) PET imaging in metastatic carcinoma, which demonstrated high clinical impact for a variety of malignancies [49]. The A20FMDV2 (NAVPNLRGDLQVLAQKVART) peptide has been derived from the foot and mouth virus, possesses high selectivity and affinity for the αvβ6 integrin’s RGD site, and can be employed as a radiotracer after being radiolabelled with the radionuclide. A scientific group radiolabelled this peptide with 4-[18F] fluorobenzoic acid and used microPET for cancer imaging. They achieved targeted cancer images of αvβ6-positive tumour cells because of the rapid uptake of radiolabelled peptide and then the selective retention of radioactivity in αvβ6-positive tumour cells. In other scientific studies, conjugated polyethylene glycol (PEG); small, monodispersed polymers; and new radiotracers: [18F] FBA-PEG28-A20FMDV2 and [18F] FBA-(PEG28)2-A20FMDV2 were generated for the improvement of pharmacokinetics. The former radiotracer exhibited improved PET-imaging even better than [18F]-FDG ([18F] fluoro-2-deoxy-D-glucose) during the BxPC-3 tumour imaging. A later study also showed a promising pharmacokinetic profile as well as tumour uptake for the [18F] FBA-PEG28-A20FMDV2 tracer. In another study, four chelators were selected and conjugated onto PEG28-A20FMDV2 for the radiolabelling of A20FMDV2 with 64Cu, but no best-suitable candidate was found [2].
The [64Cu] NOTA-αvβ6 cys-diabody was used for imaging αvβ6-specific tumours in vivo by a knockout mouse model bearing human melanoma xenografts, and the αvβ6-positive tumour cells were successfully visualised through PET imaging [50]. The A20FMDV2 peptide was also labelled with Indium-111, which showed good tumour retention and excellent discriminating tumour images by the use of biodistribution and SPECT-imaging. Several other radiotracers have also been well-studied, such as 99mTc-6-hydrazinonicotinyl (tricine) (TPPTS)-HK (an integrin αvβ6-targeting peptide); 125I/131I-labeled HBP-1; and 99mTc-SAAC-S02 (cystine knot peptide, S02, with a single amino acid chelate (SAAC) and labelled with [99mTc(H2O)3(CO)3]+). Hal and co-workers identified a novel integrin αvβ6 RGD-mimetic radioligand with high affinity and selectivity: (S)-3-(3-(3,5-dimethyl-1H-pyr-azol-1-yl) phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1yl) butanoic acid radiolabelled [3H]. However, further investigation is required to explore its pharmacokinetic profile and imaging effect [2].
The integrin family of proteins, αvβ6, have a strong potential to be considered one of the most promising therapeutic targets for cancer. αvβ6 is upregulated on multiple cancers, providing a window of opportunity for the selective delivery of effective therapies for life-threatening conditions. Even though the evidence that the expression of integrin αvβ6 appeared to be a prognostic marker in cancer for over two decades, there have been relatively few clinical trials that have investigated targeting this integrin.
An example is the Phase I/II trial [NCT01008475] described by Merck in 2014. In this research, a monoclonal antibody targeting αv integrins, in combination with irinotecan and cetuximab in K-ras wild-type metastatic colorectal cancer patients was used. Although the primary point of this trial was not met, the analysis of retrospective subgroup results suggested that patients with a high expression of αvβ6 integrin responded well to the addition of Abituzumab to the standard of care, with improved progression-free survival (PFS) and overall survival (OS) compared with those tumours of low αvβ6 expression [51]. Currently, there are two active clinical trials in which [18F]-αvβ6-BP is used to visualize the disease progression in different types of cancers: lung, breast, brain, colorectal, and a single trial with drug PLN-74809 currently developed by Pliant Therapeutics; data are summarized in Table 3. (Search of αvβ6-List Results-ClinicalTrials.gov, accessed: October 2022 [52]).
Table 3. List of active clinical trials with AvB6 in therapeutic settings and imaging. Different stages of clinical phase development are indicated. Retrieved from ClinicalTrials.gov, accessed on 10 October 2022 [52].
Undoubtedly, in order to use the integrin αvβ6 as a target for tumour treatment, a thoughtful strategy is first required. Starting from a biological molecule, an antibody, or a smaller peptide or a conjugate thereof, all expected and unexpected side effects should be considered in the assumption of the detailed mechanism of action.

This entry is adapted from the peer-reviewed paper 10.3390/ijms232012346

References

  1. Koivisto, L.; Bi, J.; Häkkinen, L.; Larjava, H. Integrin αvβ6: Structure, function and role in health and disease. Int. J. Biochem. Cell Biol. 2018, 99, 186–196.
  2. Niu, J.; Li, Z. The roles of integrin αvβ6 in cancer. Cancer Lett. 2017, 403, 128–137.
  3. Bandyopadhyay, A.; Raghavan, S. Defining the role of integrin αvβ6 in cancer. Cur. Drug Targ. 2009, 10, 645–652.
  4. Ludlow, A.; Yee, K.O.; Lipman, R.; Bronson, R.; Weinreb, P.; Huang, X.; Sheppard, D.; Lawler, J. Characterization of integrin β6 and thrombospondin-1 double-null mice. J. Cell. Mol. Med. 2005, 9, 421–437.
  5. Eberlein, C.; Kendrew, J.; McDaid, K.; Alfred, A.; Kang, J.; Jacobs, V.; Ross, S.; Rooney, C.; Smith, N.; Rinkenberger, J. A human monoclonal antibody 264RAD targeting αvβ6 integrin reduces tumour growth and metastasis, and modulates key biomarkers in vivo. Oncogene 2013, 32, 4406–4416.
  6. Bretones, G.; Delgado, M.D.; León, J. Myc and cell cycle control. Biochim. Biophys. Acta 2015, 1849, 506–516.
  7. Principe, D.R.; Doll, J.A.; Bauer, J.; Jung, B.; Munshi, H.G.; Bartholin, L.; Pasche, B.; Lee, C.; Grippo, P.J. TGF-β: Duality of function between tumor prevention and carcinogenesis. J. Nat. Cancer Inst. 2014, 106, djt369.
  8. Yamaoka, T.; Ohba, M.; Ohmori, T. Molecular-targeted therapies for epidermal growth factor receptor and its resistance mechanisms. Int. J. Mol. Sci. 2017, 18, 2420.
  9. Wang, G.; Yu, Y.; Sun, C.; Liu, T.; Liang, T.; Zhan, L.; Lin, X.; Feng, X.-H. STAT3 selectively interacts with Smad3 to antagonize TGF-β. Oncogene 2016, 35, 4388–4398.
  10. Bates, R.C.; Bellovin, D.I.; Brown, C.; Maynard, E.; Wu, B.; Kawakatsu, H.; Sheppard, D.; Oettgen, P.; Mercurio, A.M. Transcriptional activation of integrin β6 during the epithelial-mesenchymal transition defines a novel prognostic indicator of aggressive colon carcinoma. J. Clin. Investig. 2005, 115, 339–347.
  11. Cantor, D.I.; Cheruku, H.R.; Nice, E.C.; Baker, M.S. Integrin αvβ6 sets the stage for colorectal cancer metastasis. Cancer Metastasis Rev. 2015, 34, 715–734.
  12. Santibanez, J.F. Transforming growth factor-Beta and urokinase-type plasminogen activator: Dangerous partners in tumorigenesis—Implications in skin cancer. ISRN Dermatol. 2013, 2013, 597927.
  13. Mittal, V. Epithelial mesenchymal transition in tumor metastasis. Annu. Rev. Pathol. Mech. Dis. 2018, 13, 395–412.
  14. Lee, C.; Lee, C.; Lee, S.; Siu, A.; Ramos, D.M. The Cytoplasmic Extension of the Integrin β6 Subunit Regulates Epithelial–to–Mesenchymal Transition. Anticancer Res. 2014, 34, 659–664.
  15. Ahmed, N.; Pansino, F.; Baker, M.; Rice, G.; Quinn, M. Association between αvβ6 integrin expression, elevated p42/44 kDa MAPK, and plasminogen-dependent matrix degradation in ovarian cancer. J. Cell Biochem. 2002, 84, 675–686.
  16. Hecht, J.L.; Dolinski, B.M.; Gardner, H.A.; Violette, S.M.; Weinreb, P.H. Overexpression of the alphavbeta6 integrin in endometrial cancer. Appl. Immunohistochem. Mol. Morphol. 2008, 16, 543–547.
  17. Marsh, D.; Dickinson, S.; Neill, G.W.; Marshall, J.F.; Hart, I.R.; Thomas, G.J. Alpha vbeta 6 Integrin promotesthe invasion of morphoeic basal cell carcinoma through stromal modulation. Cancer Res. 2008, 68, 3295–3303.
  18. Yang, G.Y.; Xu, K.S.; Pan, Z.Q.; Zhang, Z.Y.; Mi, Y.T.; Wang, J.S.; Chen, R.; Niu, J. Integrin alpha v beta 6 mediates thepotential for colon cancer cells to colonize in and metastasize to the liver. Cancer Sci. 2008, 99, 879–887.
  19. Fontana, L.; Chen, Y.; Prijatelj, P.; Sakai, T.; Fässler, R.; Sakai, L.Y.; Rifkin, D.B. Fibronectin is required for integrin al-phavbeta6-mediated activation of latent TGF-beta complexes containing LTBP-1. FASEB J. 2005, 19, 1798–1808.
  20. Munger, J.S.; Huang, X.; Kawakatsu, H.; Griffiths, M.J.; Dalton, S.L.; Wu, J.; Pittet, J.F.; Kaminski, N.; Garat, C.; Matthay, M.A.; et al. The integrin alpha v beta 6 binds and activates latent TGF beta 1: A mech anism for regulating pulmonary inflammation and fibrosis. Cell 1999, 96, 319–328.
  21. Yokosaki, Y.; Tanaka, K.; Higashikawa, K.; Yamashita, K.; Eboshida, A. Distinct structural requirements for binding of the integrins alphavbeta6, alphavbeta3, alphavbeta5, alpha5beta1 and alpha9beta1 to osteopontin. Matrix Biol. J. Int. Soc. Matrix Biol. 2005, 24, 418–427.
  22. Annes, J.P.; Rifkin, D.B.; Munger, J.S. The integrin alphaVbeta6 binds and ac tivates latent TGFbeta3. FEBS Lett. 2002, 511, 65–68.
  23. Weinacker, A.; Chen, A.; Agrez, M.; Cone, R.I.; Nishimura, S.; Wayner, E.; Pytela, R.; Sheppard, D. Role of the integrin alpha v beta 6 in cell attachment to fibronectin. Heter ologous expression of intact and secreted forms of the receptor. J. Biol. Chem. 1994, 269, 6940–6948.
  24. Zhang, Z.Y.; Xu, K.S.; Wang, J.S.; Yang, G.Y.; Wang, W.; Wang, J.Y.; Niu, W.-B.; Liu, E.-Y.; Mi, Y.-T.; Niu, J. Integrin alphanvbeta6 acts as aprognostic indicator in gastric carcinoma. Clin. Oncol. 2008, 20, 61–66.
  25. Hazelbag, S.; Kenter, G.G.; Gorter, A.; Dreef, E.J.; Koopman, L.A.; Violette, S.M.; Weinreb, P.H.; Fleuren, G.J. Overexpression ofthe alpha v beta 6 integrin in cervical squamous cell carcinoma is a prognostic factor for decreased survival. J. Pathol. 2007, 212, 316–324.
  26. Jones, J.; Watt, F.M.; Speight, P.M. Changes in the expression of alpha v integrins in oral squamous cellcarcinomas. J. Oral Pathol. Med. 1997, 26, 63–68.
  27. Hamidi, S.; Salo, T.; Kainulainen, T.; Epstein, J.; Lerner, K.; Larjava, H. Expression of alpha(v)beta6 integrinin oral leukoplakia. Br. J. Cancer 2000, 82, 1433–1440.
  28. Thomas, G.J.; Nyström, M.L.; Marshall, J.F. Alphavbeta6 integrin in wound healing and cancer of the oral cavity. J. Oral Pathol. Med. 2006, 35, 1–10.
  29. Sipos, B.; Hahn, D.; Carceller, A.; Piulats, J.; Hedderich, J.; Kalthoff, H.; Goodman, S.L.; Kosmahl, M.; Klöppel, G. Immunohistochemicalscreening for beta6-integrin subunit expression in adenocarcinomas using a novel monoclonal antibody reveals strong up-regulation in pancreatic ductal adenocarcinomas in vivo and in vitro. Histopathology 2004, 45, 226–236.
  30. Murphy, P.A.; Begum, S.; Hynes, R.O. Tumor angiogenesis in the absence of fibronectin or its cognate integrin receptors. PLoS ONE 2015, 10, e0120872.
  31. Arihiro, K.; Kaneko, M.; Fujii, S.; Inai, K.; Yokosaki, Y. Significance of alpha 9 beta 1 and alpha v beta 6 integrin expression in breast carcinoma. Breast Cancer 2000, 7, 19–26.
  32. Katoh, D.; Nagaharu, K.; Shimojo, N.; Hanamura, N.; Yamashita, M.; Kozuka, Y.; Imanaka-Yoshida, K.; Yoshida, T. Binding of alphavbeta1 and alphavbeta6 integrins to tenascin-C induces epithelial-mesenchymal transition-like change of breast cancer cells. Oncogenesis 2013, 2, e65.
  33. Ahmed, N.; Pansino, F.; Clyde, R.; Murthi, P.; Quinn, M.A.; Rice, G.E.; Agrez, M.V.; Mok, S.; Baker, M.S. Overexpression of alpha(v)beta6 integrin in serous epithelial ovarian cancer regulates extracellular matrix degradation via the plasminogen activation cascade. Carcinogenesis 2002, 23, 237–244.
  34. Ahn, S.B.; Mohamedali, A.; Anand, S.; Cheruku, H.R.; Birch, D.; Sowmya, G.; Cantor, D.; Ranganathan, S.; Inglis, D.W.; Frank, R.; et al. Characterization of the interaction between heterodimeric alphavbeta6 integrin and urokinase plasminogen activator receptor (uPAR) using functional proteomics. J. Proteome Res. 2014, 13, 5956–5964.
  35. Wang, J.P.; Hielscher, A. Fibronectin: How its aberrant expression in tumors may improve therapeutic targeting. J. Cancer 2017, 8, 674.
  36. Liu, H.; Wu, Y.; Wang, F.; Liu, Z. Molecular imaging of integrin αvβ6 expression in living subjects. Am. J. Nucl. Med. Mol. Imaging 2014, 4, 333.
  37. Weinreb, P.H.; Simon, K.J.; Rayhorn, P.; Yang, W.J.; Leone, D.R.; Dolinski, B.M.; Pearse, B.R.; Yokota, Y.; Kawakatsu, H.; Atakilit, A.; et al. Function-blocking Integrin αvβ6Monoclonal Antibodies. J. Biol. Chem. 2004, 279, 17875–17887.
  38. Koopman Van Aarsen, L.A.; Leone, D.R.; Ho, S.; Dolinski, B.M.; McCoon, P.E.; LePage, D.J.; Kelly, R.; Heaney, G.; Rayhorn, P.; Reid, C.; et al. Antibody-Mediated Blockade of Integrin v 6 Inhibits Tumor Progression In vivo by a Transforming Growth Factor- Regulated Mechanism. Cancer Res. 2008, 68, 561–570.
  39. Olof Olsson, P.; Gustafsson, R.; Salnikov, A.V.; Göthe, M.; Zeller, K.S.; Friman, T.; Baldetorp, B.; Koopman, L.A.; Weinreb, P.H.; Violette, S.M.; et al. Inhibition of integrin αVβ6 changes fibril thickness of stromal collagen in experimental carcinomas. Cell Commun. Signal. 2018, 16, 36.
  40. Zhao, R.; Liu, X.-Q.; Wu, X.-P.; Liu, Y.-F.; Zhang, Z.-Y.; Yang, G.-Y.; Guo, S.; Niu, J.; Wang, J.-Y.; Xu, K.-S. Vascular endothelial growth factor (VEGF) enhances gastric carcinoma invasiveness via integrin alpha(v)beta6. Cancer Lett. 2010, 287, 150–156.
  41. Zhang, Z.Y.; Xu, K.-S.; He, Q.-S.; Niu, W.-B.; Wang, J.-Y.; Mi, Y.-T.; Wang, J.-S.; Qiang, G.-Q.; Yang, G.-Y.; Niu, J. Signaling and regulatory mechanisms of integrin ανβ6 on the apoptosis of colon cancer cells. Cancer Lett. 2008, 66, 209–215.
  42. Kogelberg, H.; Tolner, B.; Thomas, G.J.; Di Cara, D.; Minogue, S.; Ramesh, B.; Sodha, S.; Marsh, D.; Lowdell, M.W.; Meyer, T.; et al. Engineering a Single-Chain Fv Antibody to αvβ6 Integrin Using the Specificity-Determining Loop of a Foot-and-Mouth Disease Virus. J. Mol. Biol. 2008, 382, 385–401.
  43. Reader, C.S.; Vallath, S.; Steele, C.W.; Haider, S.; Brentnall, A.; Desai, A.; Moore, K.M.; Jamieson, N.B.; Chang, D.; Bailey, P.; et al. The integrin αvβ6 drives pancreatic cancer through diverse mechanisms and represents an effective target for therapy. J. Pathol. 2019, 249, 332–342.
  44. Kogelberg, H.; Miranda, E.; Burnet, J.; Ellison, D.; Tolner, B.; Foster, J.; Picón, C.; Thomas, G.J.; Meyer, T.; Marshall, J.F. Generation and characterization of a diabody targeting the αvβ6 integrin. PLoS ONE 2013, 8, e73260.
  45. Moore, K.M.; Desai, A.; Delgado, B.d.L.; Trabulo, S.M.D.; Reader, C.; Brown, N.F.; Murray, E.R.; Brentnall, A.; Howard, P.; Masterson, L.; et al. Integrin αvβ6-specific therapy for pancreatic cancer developed from foot-and-mouth-disease virus. Theranostics 2020, 10, 2930–2942.
  46. Busenhart, P.; Montalban-Arques, A.; Katkeviciute, E.; Morsy, Y.; van Passen, C.; Hering, L.; Atrott, K.; Lang, S.; Garzon, J.F.G.; Naschberger, E.; et al. Inhibition of integrin αvβ6 sparks T-cell antitumor response and enhances immune checkpoint blockade therapy in colorectal cancer. J. Immunother. Cancer 2022, 10, e003465.
  47. Bagati, A.; Kumar, S.; Jiang, P.; Pyrdol, J.; Zou, A.E.; Godicelj, A.; Mathewson, N.D.; Cartwright, A.N.R.; Cejas, P.; Brown, M.; et al. Integrin αvβ6-TGFβ-SOX4 pathway drives immune evasion in triple-negative breast cancer. Cancer Cell. 2021, 39, 54–67.
  48. Saleem, A.; Helo, Y.; Win, Z.; Dale, R.; Cook, J.; Searle, G.E.; Wells, P. Integrin αvβ6 Positron Emission Tomography Imaging in Lung Cancer Patients Treated with Pulmonary Radiation Therapy. Int. J. Radiat. Oncol. Biol. Phys. 2020, 107, 370–376.
  49. Hausner, S.H.; Bold, R.J.; Cheuy, L.Y.; Chew, H.K.; Daly, M.E.; Davis, R.A.; Foster, C.C.; Kim, E.J.; Sutcliffe, J.L. Preclinical Development and First-in-Human Imaging of the Integrin αvβ6 with αvβ6-Binding Peptide in Metastatic Carcinoma. Clin. Cancer Res. 2019, 25, 1206–1215.
  50. White, J.B.; Hu, L.Y.; Boucher, D.L.; Sutcliffe, J.L. ImmunoPET Imaging of αvβ6 Expression Using an Engineered Anti-αvβ6 Cys-diabody Site-Specifically Radiolabeled with Cu-64: Considerations for Optimal Imaging with Antibody Fragments. Mol. Imaging Biol. 2017, 20, 103–113.
  51. Meecham, A.; Marshall, J. Harnessing the power of foot-and-mouth-disease virus for targeting integrin alpha-v beta-6 for the therapy of cancer. Exp. Opin. Drug Disc. 2021, 16, 737–744.
  52. Search of: αvβ6—List Results—ClinicalTrials.gov. Available online: https://clinicaltrials.gov/ct2/results?cond=&term=%CE%B1v%CE%B26+&cntry=&state=&city=&dist= (accessed on 10 October 2022).
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